Zearalenone Regulates Energy Metabolism and Proliferation of Goat Endometrial Epithelial Cells through Estrogen Receptor 1.

Zearalenone (ZEN), an estrogenic mycotoxin inducing reproductive toxicity, disrupts endometrial cell function and contributes to pregnancy failure, although its endometrial toxicity mechanisms remain unclear. This study reveals that ZEN inhibits goat endometrial epithelial cells (EECs) proliferation through estrogen receptor 1 (ESR1) homodimers. ESR1 knockout reversed ZEN-induced mitochondrial structural/functional damage via the ESR1-OMA1 zinc metallopeptidase (OMA1) axis. Furthermore, ZEN suppresses glycolysis and mitochondrial pyruvate transport in goat EECs through the ESR1-pyruvate kinase isoenzyme type M2 (PKM2) pathway. Pyruvate level alterations critically influence mitochondrial function and cell proliferation, with the expression of OMA1 mediating this regulatory process. Collectively, ZEN impairs mitochondrial dynamics in goat EECs through ESR1-OMA1 signaling and disrupts energy metabolism via the ESR1-PKM2 pathway, ultimately arresting cell proliferation. These mechanistic insights into ZEN's reproductive toxicity may guide protective strategies for human and animal health.